Compounds > kynurenine
Page last updated: 2024-10-18

kynurenine and Glioma

kynurenine has been researched along with Glioma in 16 studies

Kynurenine: A metabolite of the essential amino acid tryptophan metabolized via the tryptophan-kynurenine pathway.
kynurenine : A ketone that is alanine in which one of the methyl hydrogens is substituted by a 2-aminobenzoyl group.

Glioma: Benign and malignant central nervous system neoplasms derived from glial cells (i.e., astrocytes, oligodendrocytes, and ependymocytes). Astrocytes may give rise to astrocytomas (ASTROCYTOMA) or glioblastoma multiforme (see GLIOBLASTOMA). Oligodendrocytes give rise to oligodendrogliomas (OLIGODENDROGLIOMA) and ependymocytes may undergo transformation to become EPENDYMOMA; CHOROID PLEXUS NEOPLASMS; or colloid cysts of the third ventricle. (From Escourolle et al., Manual of Basic Neuropathology, 2nd ed, p21)

Research Excerpts

ExcerptRelevanceReference
"Conversion of tryptophan to kynurenine may promote glioma growth and suppress antitumor immune response through activation of the aryl hydrocarbon receptor."8.12A prospective study of pre-diagnostic circulating tryptophan and kynurenine, and the kynurenine/tryptophan ratio and risk of glioma. ( Cote, DJ; Egan, KM; McCann, A; Midttun, Ø; Samanic, CM; Smith-Warner, SA; Stampfer, MJ; Ueland, PM; Wang, M; Yue, Y, 2022)
"Increased tryptophan metabolism via the kynurenine pathway (KP) is a key mechanism of tumoral immune suppression in gliomas."7.81Molecular imaging correlates of tryptophan metabolism via the kynurenine pathway in human meningiomas. ( Bosnyák, E; Guastella, AR; Juhász, C; Kamson, DO; Kupsky, WJ; Michelhaugh, SK; Mittal, S; Muzik, O; Robinette, NL; Varadarajan, K, 2015)
"These observations provide evidence for altered tryptophan uptake in contralateral cortical and thalamic brain regions in glioma patients after initial therapy, suggesting treatment effects on the serotonergic system."7.80Clinical significance of tryptophan metabolism in the nontumoral hemisphere in patients with malignant glioma. ( Barger, GR; Chakraborty, PK; Juhász, C; Kamson, DO; Lee, TJ; Mittal, S; Muzik, O; Robinette, NL; Snyder, M; Varadarajan, K, 2014)
"Conversion of tryptophan to kynurenine may promote glioma growth and suppress antitumor immune response through activation of the aryl hydrocarbon receptor."4.12A prospective study of pre-diagnostic circulating tryptophan and kynurenine, and the kynurenine/tryptophan ratio and risk of glioma. ( Cote, DJ; Egan, KM; McCann, A; Midttun, Ø; Samanic, CM; Smith-Warner, SA; Stampfer, MJ; Ueland, PM; Wang, M; Yue, Y, 2022)
"We examined the protein expression levels (in 73 gliomas and 48 meningiomas) of the KP rate-limiting enzymes indoleamine 2,3-dioxygenase (IDO) 1, IDO2, and tryptophan 2,3-dioxygenase (TDO2), as well as, the aryl hydrocarbon receptor (AhR), a carcinogenic transcription factor activated by KP metabolites."3.88Investigation of the aryl hydrocarbon receptor and the intrinsic tumoral component of the kynurenine pathway of tryptophan metabolism in primary brain tumors. ( Ali-Fehmi, R; Fadel, HA; Guastella, AR; Juhász, C; Kiousis, S; Klinger, NV; Kupsky, WJ; Michelhaugh, SK; Mittal, S, 2018)
"Increased tryptophan metabolism via the kynurenine pathway (KP) is a key mechanism of tumoral immune suppression in gliomas."3.81Molecular imaging correlates of tryptophan metabolism via the kynurenine pathway in human meningiomas. ( Bosnyák, E; Guastella, AR; Juhász, C; Kamson, DO; Kupsky, WJ; Michelhaugh, SK; Mittal, S; Muzik, O; Robinette, NL; Varadarajan, K, 2015)
"These observations provide evidence for altered tryptophan uptake in contralateral cortical and thalamic brain regions in glioma patients after initial therapy, suggesting treatment effects on the serotonergic system."3.80Clinical significance of tryptophan metabolism in the nontumoral hemisphere in patients with malignant glioma. ( Barger, GR; Chakraborty, PK; Juhász, C; Kamson, DO; Lee, TJ; Mittal, S; Muzik, O; Robinette, NL; Snyder, M; Varadarajan, K, 2014)
"Targeting the KP in brain tumors may represent a viable strategy likely to prevent QUIN-induced neurotoxicity and KYN and 3-HAA-mediated immune suppression."2.48The kynurenine pathway in brain tumor pathogenesis. ( Adams, S; Bessede, A; Bessesde, A; Braidy, N; Brew, BJ; Grant, R; Guillemin, GJ; Teo, C, 2012)

Research

Studies (16)

TimeframeStudies, this research(%)All Research%
pre-19900 (0.00)18.7374
1990's0 (0.00)18.2507
2000's1 (6.25)29.6817
2010's8 (50.00)24.3611
2020's7 (43.75)2.80

Authors

AuthorsStudies
Samanic, CM1
Yue, Y1
Cote, DJ1
Stampfer, MJ1
Wang, M1
McCann, A1
Midttun, Ø1
Ueland, PM1
Smith-Warner, SA1
Egan, KM1
Obara-Michlewska, M1
Ma, W1
Ye, L1
Zhong, C1
Li, J1
Ye, F1
Lv, L1
Yu, Y1
Jiang, S1
Zhou, P1
Nguyen, TT1
Shin, DH1
Sohoni, S1
Singh, SK1
Rivera-Molina, Y1
Jiang, H1
Fan, X1
Gumin, J1
Lang, FF1
Alvarez-Breckenridge, C1
Godoy-Vitorino, F1
Zhu, L1
Zheng, WJ1
Zhai, L1
Ladomersky, E1
Lauing, KL1
Alonso, MM1
Wainwright, DA1
Gomez-Manzano, C1
Fueyo, J1
Du, L1
Xing, Z1
Tao, B1
Li, T1
Yang, D1
Li, W1
Zheng, Y1
Kuang, C1
Yang, Q1
Reardon, DA1
Desjardins, A1
Rixe, O1
Cloughesy, T1
Alekar, S1
Williams, JH1
Li, R1
Taylor, CT1
Lassman, AB1
Vázquez Cervantes, GI1
Pineda, B1
Ramírez Ortega, D1
Salazar, A1
González Esquivel, DF1
Rembao, D1
Zavala Vega, S1
Gómez-Manzo, S1
Pérez de la Cruz, G1
Pérez de la Cruz, V1
Guastella, AR2
Michelhaugh, SK2
Klinger, NV1
Fadel, HA1
Kiousis, S1
Ali-Fehmi, R1
Kupsky, WJ2
Juhász, C3
Mittal, S3
Kamson, DO2
Lee, TJ1
Varadarajan, K2
Robinette, NL2
Muzik, O2
Chakraborty, PK1
Snyder, M1
Barger, GR1
Adams, S2
Teo, C2
McDonald, KL1
Zinger, A1
Bustamante, S1
Lim, CK1
Sundaram, G1
Braidy, N2
Brew, BJ2
Guillemin, GJ3
Bosnyák, E1
Bostian, AC1
Eoff, RL1
Opitz, CA1
Litzenburger, UM1
Sahm, F1
Ott, M1
Tritschler, I1
Trump, S1
Schumacher, T1
Jestaedt, L1
Schrenk, D1
Weller, M1
Jugold, M1
Miller, CL1
Lutz, C1
Radlwimmer, B1
Lehmann, I1
von Deimling, A1
Wick, W1
Platten, M1
Prendergast, GC1
Bessede, A1
Bessesde, A1
Grant, R1
Kocki, T1
Dolińska, M1
Dybel, A1
Urbańska, EM1
Turski, WA1
Albrecht, J1

Clinical Trials (2)

Trial Overview

TrialPhaseEnrollmentStudy TypeStart DateStatus
A PHASE 1 DOSE ESCALATION STUDY EVALUATING THE SAFETY AND TOLERABILITY OF PF-06840003 IN PATIENTS WITH MALIGNANT GLIOMAS[NCT02764151]Phase 117 participants (Actual)Interventional2016-09-09Terminated (stopped due to Sponsor decided to prematurely terminate the study and not to pursue marketing approval for the indication of malignant glioma.)
Tryptophan Metabolism in Human Brain Tumors[NCT02367469]105 participants (Anticipated)Observational2014-02-28Completed
[information is prepared from clinicaltrials.gov, extracted Sep-2024]

Trial Outcomes

Number of Participants With Clinically Significant Findings in Vital Signs [Part 1]

Vital signs included measurements of blood pressure and temperature (oral, tympanic, temporal or axillary). The investigator judged any clinically significant vital signs findings. (NCT02764151)
Timeframe: Baseline up to 1 year

InterventionParticipants (Count of Participants)
PF-06840003 125 MG QD0
PF-06840003 250 MG QD0
PF-06840003 250 MG BID0
PF-06840003 500 MG BID0

Number of Participants With Dose Limiting Toxicities (DLTs) [Part 1]

DLTs: Any of the following adverse events (AE) occurring in the first cycle of treatment, unless there is a clear alternative explanation. Hematologic: Grade (Gr) 4 neutropenia lasting >=5 days; febrile neutropenia; Gr>=3 neutropenic with infection; Gr>=3 thrombocytopenia with bleeding; Gr 4 thrombocytopenia. Non-Hematologic: Any toxicity attributable to PF-06840003 that resulted in administration of less than 80% of the planned doses during Cycle 1; Gr 4 non-hematologic AE; Gr 3 AE lasting >7 days despite optimal supportive care; Gr 3 central nervous system (CNS) AE regardless of duration; Gr 3 QTc prolongation (QTc >500 milliseconds) (a DLT only if persisting after correction of any reversible causes); Concurrent aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3*upper limit of normal (ULN) and total bilirubin >2*ULN. (NCT02764151)
Timeframe: Baseline to Day 28

InterventionParticipants (Count of Participants)
PF-06840003 125 MG QD0
PF-06840003 250 MG QD0
PF-06840003 250 MG BID0
PF-06840003 500 MG BID1

Plasma Endogenous Kynurenine/Tryptophan Ratio [Part 1]

The Kynurenine/Tryptophan ratio was determined by 1000*Kynurenine/Tryptophan. (NCT02764151)
Timeframe: Cycle 1 Day 1 pre-dose, and 1, 2, 4, 6, 8, 24 hours post-dose; Cycle 1 Day 4 and Day 8 pre-dose; Cycle 1 Day 15 pre-dose, and 1, 2, 4, 6, 8, 24 hours post-dose

Interventionratio (Mean)
PF-06840003 125 MG QD38.467
PF-06840003 250 MG QD53.066
PF-06840003 250 MG BID25.854
PF-06840003 500 MG BID42.463

Disease Control Rate (DCR) Based on the Immunotherapy Response Assessment for Neuro-Oncology (iRANO) Criteria [Part 1]

Disease control rate (DCR) was defined as the percentage of patients achieving CR, PR, or stable disease (SD). Overall DCR was based on iRANO criteria: CR: complete disappearance of all enhancing measurable and non-measurable disease on consecutive MRI at least 4 weeks apart, off steroid, sustained for at least 4 weeks; PR: >=50% decrease compared with baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions sustained for at least 4 weeks; SD: does not qualify for CR, PR, or progression disease, and stable clinically. (NCT02764151)
Timeframe: Weeks 8, 16, and 24

,,,
Interventionpercentage of participants (Number)
Week 8Week 16Week 24
PF-06840003 125 MG QD50.050.00.0
PF-06840003 250 MG BID33.366.70.0
PF-06840003 250 MG QD50.00.00.0
PF-06840003 500 MG BID25.025.025.0

Multiple Dose: Apparent Clearance (CL/F) of PF-06840002 and PF-06840001 [Part 1]

CL/F of PF-06840002 (Active Enantiomer) and PF-06840001 (Inactive Enantiomer) was determined by Dose/Area under the concentration-time profile from time 0 extrapolated to infinite time (AUCinf). (NCT02764151)
Timeframe: Cycle 1 Day 15 pre-dose, 1, 2, 4, 6, 8, 24 hrs post

,,,
InterventionmL/min (Geometric Mean)
PF-06840002PF-06840001
PF-06840003 125 MG QDNANA
PF-06840003 250 MG BID327.6198.2
PF-06840003 250 MG QD624.2399.1
PF-06840003 500 MG BID408.3259.5

Multiple Dose: Apparent Volume of Distribution (Vz/F) of PF-06840002 and PF-06840001 [Part 1]

Vz/F of PF-06840002 (Active Enantiomer) and PF-06840001 (Inactive Enantiomer) was determined by Dose/(AUC*kel). AUC is the area under concentration curve and kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration time curve. The analysis population included all enrolled participants treated who had sufficient information to estimate at least 1 of the PK parameters of interest. (NCT02764151)
Timeframe: Cycle 1 Day 15 pre-dose, 1, 2, 4, 6, 8, 24 hrs post

,,,
InterventionLiter (Median)
PF-06840002PF-06840001
PF-06840003 125 MG QD184.5102.6
PF-06840003 250 MG BID12872.6
PF-06840003 250 MG QD216117
PF-06840003 500 MG BID270.5162

Multiple Dose: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-06840002 and PF-06840001 [Part 1]

AUCtau of PF-06840002 (Active Enantiomer) and PF-06840001 (Inactive Enantiomer) was determined by linear/log trapezoidal method. (NCT02764151)
Timeframe: Cycle 1 Day 15 pre-dose, 1, 2, 4, 6, 8, 24 hrs post

,,,
Interventionng*hr/mL (Geometric Mean)
PF-06840002PF-06840001
PF-06840003 125 MG QDNANA
PF-06840003 250 MG BID1273021020
PF-06840003 250 MG QD668010440
PF-06840003 500 MG BID2041032080

Multiple Dose: Average Concentration for the Dosing Interval (Cav) of PF-06840002 and PF-06840001 [Part 1]

Cav of PF-06840002 (Active Enantiomer) and PF-06840001 (Inactive Enantiomer) was observed directly from data. (NCT02764151)
Timeframe: Cycle 1 Day 15 pre-dose, 1, 2, 4, 6, 8, 24 hrs post

,,,
Interventionng/mL (Geometric Mean)
PF-06840002PF-06840001
PF-06840003 125 MG QDNANA
PF-06840003 250 MG BID10601755
PF-06840003 250 MG QD278435.1
PF-06840003 500 MG BID17022673

Multiple Dose: Lowest Concentration Observed During the Dosing Interval (Cmin) of PF-06840002 and PF-06840001 [Part 1]

Cmin of PF-06840002 (Active Enantiomer) and PF-06840001 (Inactive Enantiomer) was observed directly from data. (NCT02764151)
Timeframe: Cycle 1 Day 15 pre-dose, 1, 2, 4, 6, 8, 24 hrs post

,,,
Interventionng/mL (Mean)
PF-06840002PF-06840001
PF-06840003 125 MG QDNANA
PF-06840003 250 MG BID687.31079
PF-06840003 250 MG QD15.8521.75
PF-06840003 500 MG BID16112308

Multiple Dose: Maximum Observed Plasma Concentration (Cmax) of PF-06840002 and PF-06840001 [Part 1]

Cmax of PF-06840002 (Active Enantiomer) and PF-06840001 (Inactive Enantiomer) were observed directly from data. (NCT02764151)
Timeframe: Cycle 1 Day 15 pre-dose, 1, 2, 4, 6, 8, 24 hrs post

,,,
Interventionng/mL (Geometric Mean)
PF-06840002PF-06840001
PF-06840003 125 MG QDNANA
PF-06840003 250 MG BID17632810
PF-06840003 250 MG QD779.31334
PF-06840003 500 MG BID24743978

Multiple Dose: Observed Accumulation Ratio (Rac) of PF-06840002 and PF-06840001 [Part 1]

Rac of PF-06840002 (Active Enantiomer) and PF-06840001 (Inactive Enantiomer) was determined by AUCtau (steady state) / AUCtau (single dose). (NCT02764151)
Timeframe: Cycle 1 Day 15 pre-dose, 1, 2, 4, 6, 8, 24 hrs post

,,,
Interventionratio (Geometric Mean)
PF-06840002PF-06840001
PF-06840003 125 MG QDNANA
PF-06840003 250 MG BID1.6701.717
PF-06840003 250 MG QD1.2441.163
PF-06840003 500 MG BID2.3592.304

Multiple Dose: Steady State Accumulation Ratio (Rss) of PF-06840002 and PF-06840001 [Part 1]

Rss of PF-06840002 (Active Enantiomer) and PF-06840001 (Inactive Enantiomer) was determined by AUCtau (steady state) / AUCinf (single dose). The analysis population included all enrolled participants treated who had sufficient information to estimate at least 1 of the PK parameters of interest. (NCT02764151)
Timeframe: Cycle 1 Day 15 pre-dose, 1, 2, 4, 6, 8, 24 hrs post

,,
Interventionratio (Geometric Mean)
PF-06840002PF-06840001
PF-06840003 125 MG QDNANA
PF-06840003 250 MG QD1.2891.266
PF-06840003 500 MG BID1.9611.895

Multiple Dose: Terminal Half-Life (t1/2) of PF-06840002 and PF-06840001 [Part 1]

t1/2 of PF-06840002 (Active Enantiomer) and PF-06840001 (Inactive Enantiomer) was determined by Loge(2)/kel, where kel is the terminal phase rate constant calculated by a linear regression of the log linear concentration-time curve. Only those data points judged to describe the terminal log linear decline were used in the regression. The analysis population included all enrolled participants treated who had sufficient information to estimate at least 1 of the PK parameters of interest. (NCT02764151)
Timeframe: Cycle 1 Day 15 pre-dose, 1, 2, 4, 6, 8, 24 hrs post

,,,
Interventionhr (Median)
PF-06840002PF-06840001
PF-06840003 125 MG QD5.585.505
PF-06840003 250 MG BID2.682.50
PF-06840003 250 MG QD2.902.61
PF-06840003 500 MG BID2.8852.685

Multiple Dose: Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-06840002 and PF-06840001 [Part 1]

Tmax of PF-06840002 (Active Enantiomer) and PF-06840001 (Inactive Enantiomer) were observed directly from data as time of first occurence. (NCT02764151)
Timeframe: Cycle 1 Day 15 pre-dose, 1, 2, 4, 6, 8, 24 hrs post

,,,
Interventionhr (Median)
PF-06840002PF-06840001
PF-06840003 125 MG QD3.003.00
PF-06840003 250 MG BID2.002.00
PF-06840003 250 MG QD3.033.03
PF-06840003 500 MG BID3.023.95

Number of Participants With Chemistries Laboratory Abnormalities by Severity (as Graded by National Cancer Institute [NCI] Common Terminology Criteria for Adverse Event [CTCAE] Version 4.03) [Part 1]

Following parameters were analyzed for chemistry laboratory test: Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), alkaline phosphatase, sodium, potassium, magnesium, chloride, total calcium, total bilirubin, blood urea nitrogen (BUN) or urea, creatinine, uric acid, glucose (non-fasted), albumin, and phosphorous or phosphate. Laboratory abnormalities were graded per NCI CTCAE version 4.03 and those with at least 1 participant are presented here. (NCT02764151)
Timeframe: Baseline up to 1 year

,,,
InterventionParticipants (Count of Participants)
ALT, Grade 0ALT, Grade 1ALT, Grade 3ALT, Grade 4Alkaline phosphatase, Grade 0Alkaline phosphatase, Grade 1AST, Grade 0AST, Grade 2AST, Grade 4Bilirubin (total), Grade 0Creatinine, Grade 0Creatinine, Grade 1Creatinine, Grade 2Hypercalcemia, Grade 0Hypercalcemia, Grade 1Hyperglycemia, Grade 0Hyperglycemia, Grade 1Hyperglycemia, Grade 2Hyperglycemia, Grade 3Hyperkalemia, Grade 0Hyperkalemia, Grade 3Hypermagnesemia, Grade 0Hypermagnesemia, Grade 1Hypernatremia, Grade 0Hypernatremia, Grade 1Hypoalbuminemia, Grade 0Hypoalbuminemia, Grade 1Hypoalbuminemia, Grade 2Hypocalcemia, Grade 0Hypocalcemia, Grade 1Hypocalcemia, Grade 2Hypoglycemia, Grade 0Hypoglycemia, Grade 1Hypokalemia, Grade 0Hypokalemia, Grade 1Hypomagnesemia, Grade 0Hypomagnesemia, Grade 1Hyponatremia, Grade 0Hyponatremia, Grade 1Hyponatremia, Grade 3Hypophosphatemia, Grade 0Hypophosphatemia, Grade 2
PF-06840003 125 MG QD200020200202011110020202020020020202020020
PF-06840003 250 MG BID300030300312030300030303030003030122111130
PF-06840003 250 MG QD211031310404040040040404031031031404040040
PF-06840003 500 MG BID700162701807180142171717152161180448071062

Number of Participants With Hematology Laboratory Abnormalities by Severity (as Graded by National Cancer Institute [NCI] Common Terminology Criteria for Adverse Event [CTCAE] Version 4.03) [Part 1]

Following parameters were analyzed for hematology laboratory test: hemoglobin, platelets, white blood cell (WBC), absolute neutrophils, absolute lymphocytes, absolute monocytes, absolute eosinophils, and absolute basophils. Laboratory abnormalities were graded per NCI CTCAE version 4.03 and those with at least 1 participant are presented here. (NCT02764151)
Timeframe: Baseline up to 1 year

,,,
InterventionParticipants (Count of Participants)
Anemia, Grade 0Anemia, Grade 1Anemia, Grade 2Hemoglobin increased, Grade 0Lymphocyte count increased, Grade 0Lymphopenia, Grade 0Lymphopenia, Grade 1Lymphopenia, Grade 2Lymphopenia, Grade 3Neutrophils (absolute), Grade 0Neutrophils (absolute), Grade 1Neutrophils (absolute), Grade 2Platelets, Grade 0Platelets, Grade 1WBC, Grade 0WBC, Grade 1WBC, Grade 2
PF-06840003 125 MG QD10122110011020200
PF-06840003 250 MG BID03033101120130111
PF-06840003 250 MG QD22044211031022310
PF-06840003 500 MG BID26088510271053611

Number of Participants With TEAEs by Severity (as Graded by National Cancer Institute [NCI] Common Terminology Criteria for Adverse Event [CTCAE] Version 4.03) [Part 1]

Treatment-emergent AEs were those with initial onset or increasing in severity after the first dose of study treatment. AEs were graded by the investigator according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03: Grade 3: severe AE; Grade 4: life-threatening consequences, urgent intervention indicated; Grade 5: death related to AE. (NCT02764151)
Timeframe: Baseline up to 1 year

,,,
InterventionParticipants (Count of Participants)
Grade 3 or 4Grade 5
PF-06840003 125 MG QD00
PF-06840003 250 MG BID10
PF-06840003 250 MG QD10
PF-06840003 500 MG BID20

Number of Participants With Treatment-Emergent Adverse Events (TEAEs) [Part 1]

An AE was any untoward medical occurrence in a clinical investigation patient administered a product or medical device; the event needed not necessarily have a causal relationship with the treatment or usage. TEAEs were those with initial onset or increasing in severity after the first dose of study treatment. (NCT02764151)
Timeframe: Baseline up to 1 year

,,,
InterventionParticipants (Count of Participants)
All-causality TEAEsTreatment-related TEAEs
PF-06840003 125 MG QD21
PF-06840003 250 MG BID32
PF-06840003 250 MG QD44
PF-06840003 500 MG BID87

Objective Response Rate (ORR) [Part 1]

Objective response rate (ORR), defined as the percentage of patients achieving complete response (CR) or partial response (PR) as assessed by Macdonald criteria: CR: complete disappearance of all enhancing measurable and non-measurable disease on consecutive MRI at least 4 weeks apart, off steroid, sustained for at least 4 weeks; PR: >=50% decrease compared with baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions sustained for at least 4 weeks. (NCT02764151)
Timeframe: Weeks 8, 16, and 24

,,,
InterventionPercentage of Participants (Number)
Week 8Week 16Week 24
PF-06840003 125 MG QD0.000.000.00
PF-06840003 250 MG BID0.000.000.00
PF-06840003 250 MG QD0.000.000.00
PF-06840003 500 MG BID0.000.000.00

Plasma Kynurenine and Tryptophan [Part 1]

The levels of Kynurenine and Tryptophan in blood samples were determined using the qualified analytical method. (NCT02764151)
Timeframe: Cycle 1 Day 1 pre-dose, and 1, 2, 4, 6, 8, 24 hours post-dose; Cycle 1 Day 4 and Day 8 pre-dose; Cycle 1 Day 15 pre-dose, and 1, 2, 4, 6, 8, 24 hours post-dose

,,,
Interventionmicromolar (Mean)
KynurenineTryptophan
PF-06840003 125 MG QD1.54548.15
PF-06840003 250 MG BID1.14436.77
PF-06840003 250 MG QD2.18529.55
PF-06840003 500 MG BID1.52333.10

Single Dose: Apparent Clearance (CL/F) of PF-06840002 and PF-06840001 [Part 1]

CL/F of PF-06840002 (Active Enantiomer) and PF-06840001 (Inactive Enantiomer) was determined by Dose/Area under the concentration-time profile from time 0 extrapolated to infinite time (AUCinf). The analysis population included all enrolled participants treated who had sufficient information to estimate at least 1 of the PK parameters of interest. (NCT02764151)
Timeframe: Cycle 1 Day 1 pre-dose, 1, 2, 4, 6, 8, 24 and 72 hours post Cycle 1 Day 1 dose

,,
InterventionMilliliter per minute (mL/min) (Geometric Mean)
PF-06840002PF-06840001
PF-06840003 125 MG QDNANA
PF-06840003 250 MG QD751.6454.6
PF-06840003 500 MG BID1561965.4

Single Dose: Apparent Volume of Distribution (Vz/F) of PF-06840002 and PF-06840001 [Part 1]

Vz/F of PF-06840002 (Active Enantiomer) and PF-06840001 (Inactive Enantiomer) was determined by Dose/(AUC*kel). AUC is the area under concentration curve and kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration time curve. The analysis population included all enrolled participants treated who had sufficient information to estimate at least 1 of the PK parameters of interest. (NCT02764151)
Timeframe: Cycle 1 Day 1 pre-dose, 1, 2, 4, 6, 8, 24 and 72 hours post Cycle 1 Day 1 dose

,,
InterventionLiter (Geometric Mean)
PF-06840002PF-06840001
PF-06840003 125 MG QDNANA
PF-06840003 250 MG QD228.4129.3
PF-06840003 500 MG BID277.2159.6

Single Dose: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-06840002 and PF-06840001 [Part 1]

AUCtau of PF-06840002 (Active Enantiomer) and PF-06840001 (Inactive Enantiomer) was determined by linear/log trapezoidal method. (NCT02764151)
Timeframe: Cycle 1 Day 1 pre-dose, 1, 2, 4, 6, 8, 24 and 72 hours post Cycle 1 Day 1 dose

,,,
Interventionnanogram*hour per milliliter (ng*hr/mL) (Geometric Mean)
PF-06840002PF-06840001
PF-06840003 125 MG QDNANA
PF-06840003 250 MG BID760612280
PF-06840003 250 MG QD53568999
PF-06840003 500 MG BID865313910

Single Dose: Area Under the Plasma Concentration-Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of PF-06840002 and PF-06840001 [Part 1]

AUCinf of PF-06840002 (Active Enantiomer) and PF-06840001 (Inactive Enantiomer) was determined by AUClast + (Clast/kel), where AUClast is the area under the concentration-time profile from time zero to the time of the last quantifiable concentration, Clast is the predicted serum concentration at the last quantifiable time point estimated from the log linear regression analysis and kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration time curve. The analysis population included all enrolled participants treated who had sufficient information to estimate at least 1 of the PK parameters of interest. (NCT02764151)
Timeframe: Cycle 1 Day 1 pre-dose, 1, 2, 4, 6, 8, 24 and 72 hours post Cycle 1 Day 1 dose

,,
Interventionng*hr/mL (Geometric Mean)
PF-06840002PF-06840001
PF-06840003 125 MG QDNANA
PF-06840003 250 MG QD55499174
PF-06840003 500 MG BID53438645

Single Dose: Area Under the Plasma Concentration-time Profile From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of PF-06840002 and PF-06840001 [Part 1]

AUClast of PF-06840002 (Active Enantiomer) and PF-06840001 (Inactive Enantiomer) was determined by linear/log trapezoidal method. (NCT02764151)
Timeframe: Cycle 1 Day 1 pre-dose, 1, 2, 4, 6, 8, 24 and 72 hours post Cycle 1 Day 1 dose

,,,
Interventionnanogram*hour per milliliter (ng*hr/mL) (Geometric Mean)
PF-06840002PF-06840001
PF-06840003 125 MG QDNANA
PF-06840003 250 MG BID1334021670
PF-06840003 250 MG QD45177626
PF-06840003 500 MG BID1772028250

Single Dose: Maximum Observed Plasma Concentration (Cmax) of PF-06840002 and PF-06840001 [Part 1]

Cmax of PF-06840002 (Active Enantiomer) and PF-06840001 (Inactive Enantiomer) were observed directly from data. (NCT02764151)
Timeframe: Cycle 1 Day 1 pre-dose, 1, 2, 4, 6, 8, 24 and 72 hours post Cycle 1 Day 1 dose

,,,
Interventionnanograms per milliliter (ng/mL) (Geometric Mean)
PF-06840002PF-06840001
PF-06840003 125 MG QDNANA
PF-06840003 250 MG BID11351763
PF-06840003 250 MG QD775.01309
PF-06840003 500 MG BID14072286

Single Dose: Terminal Half-Life (t1/2) of PF-06840002 and PF-06840001 [Part 1]

t1/2 of PF-06840002 (Active Enantiomer) and PF-06840001 (Inactive Enantiomer) was determined by Loge(2)/kel, where kel is the terminal phase rate constant calculated by a linear regression of the log linear concentration-time curve. Only those data points judged to describe the terminal log linear decline were used in the regression. The analysis population included all enrolled participants treated who had sufficient information to estimate at least 1 of the PK parameters of interest. (NCT02764151)
Timeframe: Cycle 1 Day 1 pre-dose, 1, 2, 4, 6, 8, 24 and 72 hours post Cycle 1 Day 1 dose

,,
Interventionhr (Mean)
PF-06840002PF-06840001
PF-06840003 125 MG QDNANA
PF-06840003 250 MG QD3.7733.580
PF-06840003 500 MG BID2.0901.943

Single Dose: Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-06840002 and PF-06840001 [Part 1]

Tmax of PF-06840002 (Active Enantiomer) and PF-06840001 (Inactive Enantiomer) were observed directly from data as time of first occurence. (NCT02764151)
Timeframe: Cycle 1 Day 1 pre-dose, 1, 2, 4, 6, 8, 24 and 72 hours post Cycle 1 Day 1 dose

,,,
Interventionhour (hr) (Median)
PF-06840002PF-06840001
PF-06840003 125 MG QD1.582.50
PF-06840003 250 MG BID1.952.05
PF-06840003 250 MG QD1.512.05
PF-06840003 500 MG BID3.023.98

Steady-State Trough Level Ratio [Part 1]

Steady-State trough level ratio was determined by cerebrospinal fluid (CSF)/Plasma. CSF/Plasma ratio was calculated based on the unbound concentration of each analyte. The analysis population included all enrolled participants treated who had sufficient information to estimate at least 1 of the PK parameters of interest. (NCT02764151)
Timeframe: Baseline and Day 15

,
Interventionratio (Mean)
PF-06840002PF-06840001
PF-06840003 250 MG BID1.000.89
PF-06840003 500 MG BID1.000.88

Reviews

2 reviews available for kynurenine and Glioma

ArticleYear
The tryptophan metabolism, kynurenine pathway and oxidative stress - implications for glioma pathobiology.
    Neurochemistry international, 2022, Volume: 158

    Topics: Brain Neoplasms; Glioma; Humans; Indoleamine-Pyrrole 2,3,-Dioxygenase; Kynurenine; Oxidative Stress;

2022
The kynurenine pathway in brain tumor pathogenesis.
    Cancer research, 2012, Nov-15, Volume: 72, Issue:22

    Topics: Animals; Brain Neoplasms; Glioma; Humans; Kynurenine; Signal Transduction

2012

Trials

1 trial available for kynurenine and Glioma

ArticleYear
A phase 1 study of PF-06840003, an oral indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor in patients with recurrent malignant glioma.
    Investigational new drugs, 2020, Volume: 38, Issue:6

    Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Central Nervous System Neoplasms; Female; Glioma; Hu

2020

Other Studies

13 other studies available for kynurenine and Glioma

ArticleYear
A prospective study of pre-diagnostic circulating tryptophan and kynurenine, and the kynurenine/tryptophan ratio and risk of glioma.
    Cancer epidemiology, 2022, Volume: 76

    Topics: Case-Control Studies; Follow-Up Studies; Glioma; Humans; Kynurenine; Prospective Studies; Tryptophan

2022
Kynurenine produced by tryptophan 2,3-dioxygenase metabolism promotes glioma progression through an aryl hydrocarbon receptor-dependent signaling pathway.
    Cell biology international, 2022, Volume: 46, Issue:10

    Topics: Animals; Dioxygenases; Glioma; Kynurenine; Mice; Phosphatidylinositol 3-Kinases; Receptors, Aryl Hyd

2022
Reshaping the tumor microenvironment with oncolytic viruses, positive regulation of the immune synapse, and blockade of the immunosuppressive oncometabolic circuitry.
    Journal for immunotherapy of cancer, 2022, Volume: 10, Issue:7

    Topics: Animals; CD8-Positive T-Lymphocytes; Glioma; Humans; Indoleamine-Pyrrole 2,3,-Dioxygenase; Kynurenin

2022
Both IDO1 and TDO contribute to the malignancy of gliomas via the Kyn-AhR-AQP4 signaling pathway.
    Signal transduction and targeted therapy, 2020, 02-21, Volume: 5, Issue:1

    Topics: Animals; Aquaporin 4; Carcinogenesis; Female; Glioma; Humans; Indoleamine-Pyrrole 2,3,-Dioxygenase;

2020
Kynurenine Monooxygenase Expression and Activity in Human Astrocytomas.
    Cells, 2021, 08-08, Volume: 10, Issue:8

    Topics: Adult; Astrocytoma; Brain Neoplasms; Cell Line, Tumor; Female; Gene Expression Regulation, Enzymolog

2021
Investigation of the aryl hydrocarbon receptor and the intrinsic tumoral component of the kynurenine pathway of tryptophan metabolism in primary brain tumors.
    Journal of neuro-oncology, 2018, Volume: 139, Issue:2

    Topics: Antineoplastic Agents; Brain Neoplasms; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Gl

2018
Clinical significance of tryptophan metabolism in the nontumoral hemisphere in patients with malignant glioma.
    Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2014, Volume: 55, Issue:10

    Topics: Adult; Aged; Brain; Brain Neoplasms; Female; Glioma; Humans; Kynurenine; Magnetic Resonance Imaging;

2014
Involvement of the kynurenine pathway in human glioma pathophysiology.
    PloS one, 2014, Volume: 9, Issue:11

    Topics: Antigens, CD; Antigens, Differentiation, Myelomonocytic; Astrocytes; Biosynthetic Pathways; Brain Ne

2014
Molecular imaging correlates of tryptophan metabolism via the kynurenine pathway in human meningiomas.
    Neuro-oncology, 2015, Volume: 17, Issue:9

    Topics: Adolescent; Adult; Aged; Aged, 80 and over; Brain; Child; Female; Glioma; Humans; Kynurenine; Male;

2015
Aberrant Kynurenine Signaling Modulates DNA Replication Stress Factors and Promotes Genomic Instability in Gliomas.
    Chemical research in toxicology, 2016, 09-19, Volume: 29, Issue:9

    Topics: DNA Replication; Genomic Instability; Glioma; Humans; Kynurenine; Neoplasms; Signal Transduction

2016
An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor.
    Nature, 2011, Oct-05, Volume: 478, Issue:7368

    Topics: Animals; Autocrine Communication; Brain Neoplasms; Cell Line, Tumor; Cell Survival; Disease Progress

2011
Cancer: Why tumours eat tryptophan.
    Nature, 2011, Oct-12, Volume: 478, Issue:7368

    Topics: Animals; Brain Neoplasms; Glioma; Humans; Kynurenine; Receptors, Aryl Hydrocarbon

2011
Regulation of kynurenic acid synthesis in C6 glioma cells.
    Journal of neuroscience research, 2002, Jun-01, Volume: 68, Issue:5

    Topics: 4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid; Animals; Buffers; Calcium; Glioma; Gluta

2002